This invention relates to vitamin D compounds useful in treating and/or preventing secondary hyperparathyroidism and/or the symptoms thereof, and more particularly to the use of the vitamin D compound 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 to treat and/or prevent secondary hyperparathyroidism and/or the symptoms thereof.
Renal disease has become an increasingly important health problem in virtually every country in the world including highly developed countries such as the United States. Presently there are about 250,000 patients on renal dialysis who have lost almost complete use of their kidneys. There are approximately ten times this number of patients who have lost some degree of renal function due to renal disease and are progressing, to complete renal failure. Renal failure is evidenced by a decreased glomeruli filtration rate (GFR) from a high value of 110 ml/minute/1.73 m2 to 30 ml/minute/1.73 m2 where dialysis is often initiated.
Many factors contribute to the development of renal disease. High blood pressure is one of the significant contributors, as is having Type I or Type II diabetes. Current treatments for renal failure are limited to hemodialysis, an extremely expensive procedure that currently is supported by federal governments because individuals typically cannot afford this procedure on their own. The annual cost of renal disease in the United States alone is over $42 billion. Accordingly, effective methods for preventing renal disease and treating symptoms thereof would not only provide a major health benefit but would also provide a major economic benefit.
It is now universally accepted that vitamin D must first be 25-hydroxylated in the liver and subsequently 1α-hydroxylated in the kidney before it can function. (See DeLuca, “Vitamin D: The vitamin and the hormone,” Fed. Proc. 33, 2211-2219, 1974). These two reactions produce the final active form of vitamin D, namely 1α,25-(OH)2D3. (See DeLuca & Schnoes, “Vitamin D; Recent advances,” Ann. Rev. Biochem. 52, 411-439, 1983). This compound then stimulates a number of physiological processes including: stimulating the intestine to absorb calcium, stimulating the kidney to reabsorb calcium, stimulating the intestine to absorb phosphate, and stimulating, bone to mobilize calcium when signaled by high parathyroid hormone (PTH) levels. These actions result in a rise in plasma calcium and phosphorus levels that bring about the healing of bone lesions such as rickets and osteomalacia and prevent the neurological disorder of hypocalcemic tetany.
Secondary hyperparathyroidism is a universal complication in patients with chronic renal failure. Low levels of 1α,25-(OH)2D3 and phosphate retention are responsible for the development of secondary hyperparathyroidism. Low levels of circulating 1α,25-(OH)2D3 are the result of impaired kidney function resulting in the patient's inability to convert 25-hydroxy-vitamin D3 to 1α,25-dihydroxyvitamin D3. As a result of low levels of circulating 1α,25-(OH)2D3, intestinal calcium absorption is minimal which subsequently results in insufficient serum calcium levels. When the parathyroid glands sense a low level of serum calcium, the parathyroid glands secrete PTH which causes calcium to be mobilized from bone to regulate serum calcium. Left unchecked, this abnormal secretion of PTH will lead to the development of renal osteodystrophy. High PTH levels can also lead to: 1) weakening, of the bones; 2) calciphylaxis (when calcium forms clumps in the skin and lead to ulcers and potentially death of surrounding tissue); 3) cardiovascular complications; 4) abnormal fin and sugar metabolism; 5) itching (pruritis); and 6) low blood counts (anemia).
1α,25-dihydroxyvitamin D3 has been used as a therapeutic for hyperparathyroidism in patients with renal diseases. In the treatment of secondary hyperparathyroidism of renal osteodystrophy, it is well known that 1α,25-dihydroxyvitamin D3 binds to the vitamin D receptor (VDR) located in the parathyroid glands to suppress both growth and proliferation of the parathyroid cells and expression of the preproparathyoid gene. (See Demay et al., “Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-hydroxyvitamin D3.” Proc. Natl. Acad. Sci. USA 89, 8097-8101, 1992; and Darwish & DeLuca, “Identification of a transcription factor that binds to the promoter region of the human parathyroid hormone gene,” Arch. Biochem. Biophys. 355, 123-130, 1999). Because of its ability to suppress parathyroid hormone (PTH), 1,25-(OH)2D3 has been used with success in the treatment of secondary hyperparathyroidism. (See Slatopolsky et al., “Marked Suppression of Secondary Hyperparathyroidism by Intravenous Administration of 1,25-dihydroxycholecalciferol in Uremic Patients,” J. Clin. Invest. 74:2136-2143, 1984). The use of 1α,25-dihydroxyvitamin D3 in the treatment of secondary hyperparathyroidism of renal osteodystrophy is often precluded, however, by the development of hypercalcemia resulting from 1α,25-dihydroxyvitamin D3's potent action on intestinal calcium absorption and bone mineral calcium mobilization.
As noted previously, secondary hyperparathyroidism typically will occur in patients undergoing renal dialysis. Chronic renal failure is the most common cause of secondary hyperparathyroidism. Failing kidneys do not convert enough vitamin D to its active form and do not adequately excrete phosphate. When this happens, insoluble calcium phosphate forms in the body and removes calcium from circulation. Ultimately, this leads to hypocalcemia and secondary hyperparathyroidism.
Secondary hyperparathyroidism also can result from gastrointestinal malabsorption syndromes (e.g., chronic pancreatitis, small bowel disease, and malabsorption-dependent bariatric surgery in which the intestines do not absorb vitamins and minerals properly), where these syndromes may result in insufficient, absorption of the fat soluble vitamin D. When vitamin D is insufficiently absorbed, hypocalcemia may develop and a subsequent increase in PTH secretion may result where the body attempts to increase serum calcium levels. However, hypocalcemia and secondary hyperparathyroidism also may appear in the early stages of renal disease due to low levels of 1,25(OH)2D3. Other less common causes of secondary hyperparathyroidism are long-term lithium therapy, vitamin D deficiency, malnutrition, vitamin D-resistant rickets, or hypermagnesemia (i.e., abnormally high blood magnesium levels).
Symptoms of secondary hyperparathyroidism include increased, levels of serum PTH, serum phosphorus, and serum creatinine. Less overt symptoms include bone and joint pain, bone deformities, broken bones (fractures), swollen joints, kidney stones, increased urination, muscle weakness and pain, nausea, and loss of appetite. Other less common symptoms include fatigue, upper abdominal pain, and depression.
Treatment of secondary hyperparathyroidism typically involves addressing the underlying cause of the hypocalcemia. In patients with chronic renal failure, treatment consists of dietary restriction of phosphorus, supplements with an active form of vitamin D such as calcitriol, Hectorol®, or Zemplar®(paricalcitol), and phosphate binders which can be divided into calcium-based binders and non-calcium based binders. A newer class of medication is calcimimetics, one of which is commercially available as Sensipar®(cinacalcet) in the United States and Australia, and as Mimpara® in the European Union. Calcimimetics have achieved positive responses and are FDA approved for use in patients on dialysis, but have not been approved for use in chronic kidney disease pre-dialysis because, among other concerns, they can increase phosphorus levels. Most patients with hyperparathyroidism secondary to chronic kidney disease will improve after renal transplant, but many will continue to have a degree of residual hyperparathyroidism (i.e., tertiary hyperparathyroidism) post-transplant with associated risk of bone loss.
Although serum phosphorus is usually normal in patients with early renal insufficiency, phosphate restriction can reduce secondary hyperparathyroidism. Dietary phosphate restriction increases 1,25-(OH)2D3 levels. (See Portale et al., “Effect of Dietary Phosphorus on Circulating Concentrations of 1,25-dihydroxyvitamin D and Immunoreactive Parathyroid Hormone in Children with Moderate Renal Insufficiency,” J. Clin. Invest. 73:1580-1589, 1984). This in turn decreases PTH by directly suppressing PTH gene transcription and by increasing intestinal calcium absorption. In later stages of renal failure, the extent of hyperparathyroidism and 1,25-(OH)2D3 deficiency increases, and phosphate restriction has little effect on 1,25-(OH)2D3 levels. (See Lopez-Hilker et al., “Phosphorus Restriction Reverses Hyperparathyroidism in Uremia Independent of Changes in Calcium and Calcitriol,” Am. J. Physiol. 259:F432-F437, 1990). This is presumably due to the decreased renal mass available for 1,25-(OH)2D3 synthesis.
Several vitamin D analogs with low calcemic activity have been found to be nearly as effective as 1,25-(OH)2D3 in suppressing PTH secretion by cultured bovine parathyroid cells. These include 22-oxacalcitriol (OCT), (Brown et al., “The Non-Calcemic Analog of Vitamin D, 22-oxacalcitriol (OCT) Suppresses Parathyroid Hormone Synthesis and Secretion,” J. Clin. Invest. 84:728-732, 1989), as well as 1,25-(OH)2-16-ene-23-yne-D3, 1,25-(OH)2-24-dihomo-D3, and 1,25-(OH)2-24-trihomo-22-ene-D3. 22-oxacalcitriol has been examined in detail for this action in vivo. (See Brown et al., “Selective Vitamin U Analogs and their Therapeutic Applications,” Sem. Nephrol 14:156-174, 1994, reporting that 22-oxacalcitriol, despite its rapid clearance in vivo, could suppress PTH mRNA). Low, submaximal doses of calcitriol and OCT exhibited comparable inhibition. OCT also has been shown to suppress serum PTH in uremic rats and dogs.
Another analog of 1,25-(OH)2D3 with low calcemic and phosphatemic action is 19-nor-1,25-(OH)2D2. This analog of calcitriol has the carbon 28 and the double bond at carbon 22 that are characteristic of vitamin D2 compounds, but it lacks carbon 19 and the exocyclic double bond found in all natural vitamin D compounds. Studies in vitro utilizing a primary culture of bovine parathyroid cells demonstrated that 19-nor-1,25-(OH)2D2 had a similar suppressive effect on PTH as 1,25-(OH)2D3. A 52% suppression on PTH release was obtained with 19-nor-1,25-(OH)2D2 at 10−7M. There was no significant difference in the suppressive effect of PTH secretion between the two compounds.
Thereafter, preliminary studies were performed in vivo to determine the calcemic activity of 19-nor-1,25-(OH)2D2. It was found that 1,25-(OH)2D3 (10 ng/rat/10 days) increased serum calcium to the same magnitude as 19-nor-1,25-(OH2) D2 (100 ng/rat/10 days). Because of this, three different doses of 1,25-(OH)2D3 (2, 4, and 8 ng) and 19-nor-1,25-(OH)2D2 (8, 25, and 75 ng) were selected for chronic studies. After two months of renal insufficiency, the animals received the above two compounds at the three indicated doses, four times, during a period of eight days. As expected. 1,25-(OH)2D3 suppressed pre-pro-PTH mRNA and PTH secretion. However, this decrease was statistically significant only with a 8 ng dose, and this dose induced hypercalcemia and hyperphosphatemia. On the other hand, none of the doses of 19-nor-1,25-(OH)2D2 produced statistically significant changes in serum ionized calcium or serum phosphorus.
19-nor-1α,25(OH)2D2 is also known as Paricalcitol and 19-nor-1α,25-dihydroxy-ergocalciferol. Paricalcitol injection is available commercially as Zemplar® from Abbott Laboratories, Abbott Park, Ill. A paricalcitol (Zemplar®) injection is described in U.S. Pat. No. 6,136,799 and has been approved by the FDA and is marketed for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure (CKD Stage 5 or end-stage renal disease (ESRD), GFR <15 mL/min/1.73 m2). This intravenous formulation contains 2-10 micrograms/milliliter of paricalcitol, 30% (viv) propylene glycol, 20% (v/v) ethanol and approximately 50% (v/v) water. Studies indicate that paricalcitol injection suppresses elevated levels of PTH with minimal effect on serum calcium and phosphorus levels. Since its approval by the FDA in April of 1998, it is estimated that approximately 200,000 patients have received at least one dose of paricalcitol injection. Clinically, the safety and efficacy of paricalcitol injection to treat secondary hyperparathyroidism are well established.
Hyperphosphatemia is also a persistent problem in chronic hemodialysis patients and can be further aggravated by therapeutic doses of 1,25-(OH)2D3. (See Delmez et al., “Hyperphosphatemia: Its Consequences and Treatment in Patients with Chronic Renal Disease,” Am. J. Kidney Dis. 19:303-317, 1992; and Quarks et al., “Prospective trial of Pulse Oral versus Intravenous Calcitriol Treatment of Hyperparathyroidism in ESRD,” Kidney Int. 45:1710-1721, 1994). In addition, the control of phosphate absorption with large doses of calcium carbonate only increases the risk of hypercalcemia from 1,2-(OH)2D3 therapy. (See Meyrier et al., “The Influence of a High Calcium Carbonate Intake on Bone Disease in Patients undergoing Hemodialysis,” Kidney Int. 4:146-153, 1973; Moriniere of al., “Substitution of Aluminum Hydroxide by High Doses of Calcium Carbonate in Patients on Chronic Hemodialysis: Disappearance of Hyperaluminaemia and Equal Control of Hyperparathyroidism,” Proc. Eur. Dial Transplant Assoc. 19:784-787, 1983; and Slatopolsky et al., “Calcium Carbonate as a Phosphate Binder in Patients with Chronic Renal Failure Undergoing Dialysis,” New Engl. J. Med. 315:157-161, 1986). Thus, an analog of 1,25-(OH)2D3 that can suppress PTH with minor effects on calcium and phosphate metabolism would be an ideal tool for the control and treatment of secondary hyperparathyroidism.
Another vitamin D analog, namely, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (referred to in the literature as “2MD”) is also known to suppress PTH production. (See U.S. Published Application No. 2011/0034426A1). Although it would therefore appear to be a candidate for treating secondary hyperparathyroidism, it is also well known from U.S. Pat. No. 5,843,928 that 2MD has very potent calcemic activity. 2MD significantly increases bone calcium mobilization activity to a level likely to be 10-100 times that of 1α,25-(OH)2D3 while also exhibiting a modest increase in intestinal calcium transport activity. Due to this highly selective activity for the mobilization of calcium from hone, the compound 2MD was never seriously considered as a pharmaceutical agent for treating secondary hyperparathyroidism until now.